anticonvulsants have differing modes of action and therefore failure to
respond to one does not imply that others may not work

Introduction

Tissue
injury is usually accompanied by pain and is described as neuropathic if the
initiating injury occurs to neural tissue.
After injury occurs, symptoms are initially experienced distal to the
site of injury: by contrast in non-neuropathic
pain (nociceptive pain) symptoms are apparent, at least initially, at the site
of injury. With time the margins between these types become blurred and each may
coexist with the other. The
consequence of neural injury is change in neural function both at the site of
injury and proximal to it with the symptoms produced being manifestations of
neural over or under activity. Typical features of neuropathic pain, regardless
of the causal injury, include shooting / lancinating pain, burning pain,
paraesthesia / dysaesthesia, numbness and allodynia (pain produced by a normally
non-painful stimulus).

In addition
to differing symptoms experienced with neuropathic and nociceptive pain, there
are differences in those therapeutic agents which can produce pain relief.
For example, it is accepted that nociceptive pain may be relieved by
morphine and non-steroidal anti-inflammatory drugs (NSAIDs). However, with
neuropathic pain some studies suggest analgesia with morphine (1,2) and
NSAIDs (3,4) , while others demonstrate no analgesia with morphine (5,
6) or NSAIDs (7,8) .

The aim of
this article is to highlight current therapeutic options for the treatment of
neuropathic pain.

Capsaicin

It has been
recognised for almost 150 years that the topical application of extracts of the
capsicum pepper can produce pain relief (9) .
It is now recognised that the active pain killing constituent of the chili
pepper is capsaicin, which when repeatedly applied topically in
appropriate concentration causes reversible depletion of the neurotransmitter
substance P (SP) from the sensory nerve endings (10) and hence pain relief, which may take several weeks to occur.
Topical application of capsaicin has been shown to reduce the pain of a
variety of conditions, including post herpetic neuralgia (11 - 13) ,
painful diabetic neuropathy (14 - 16) , chronic distal painful
polyneuropathy (17) , surgical
neuropathic pain (18) , post mastectomy syndrome (19) and osteoarthritis ( 20 - 23) .
The major side effect is that of burning discomfort which may lead to
poor patient compliance. The addition of glyceryl trinitrate (GTN) to capsaicin
reduces the burning discomfort associated with application (24,25) and
may improve compliance. GTN is also
known to have an anti-inflammatory effect (26, 27) and this may augment the analgesia from the capsaicin.

Tricyclic antidepressants

It is widely
accepted that oral tricyclic antidepressants (TCAs) have an analgesic effect in
neuropathic pain (28, 29)
with evidence of efficacy existing for amitriptyline (30 - 34) , imipramine (35),
desimipramine (36 - 38) and
clomipramine (39, 40) . This
analgesic effect is independent of their antidepressant effect (41) and may be dose related (42,43) .
TCAs have an effect of 5 hydroxytriptamine release (44) , the
noradrenergic pathways (45) and
a sodium channel blocking effect (46), the later effect being shared
by the local anaesthetic and anticonvulsant groups.

Unfortunately,
the undoubted analgesic effect of the TCAs is tempered by their side effect
profiles with somnolence and dry mouth being the predominant side-effects.
Recent work has highlighted a potential analgesic effect of topical
doxepin, a TCA, in neuropathic pain (47,48) .
The topical application of doxepin is associated with few side effects,
and particularly central side-effects. Animal
work has suggested a potential peripheral action of TCAs (49, 50) and may explain the analgesis seen in human studies.

Anticonvulsants

It has long
been appreciated that there a similarities between epilepsy and neuropathic pain
(in 1885 Trousseau described trigeminal neuralgia as "epileptiform neuralgia 51)
) and that drugs that are effective in reducing seizure frequency may also
have an analgesic effect in neuropathic pain (52, 53) .
The first report of analgesia with an anticonvulsant in neuropathic pain
was with phenytoin in 1942 (54).
Subsequent randomised controlled trials (RCTs) has confirmed this case
report evidence with phenytoin (55, 56) .
In 1962 case report evidence of analgesia with carbamazepine emerged (57)
, with subsequent support from RCTs in trigeminal neuralgia (58)
and painful diabetic neuropathy (59) .
Carbamazepine remains the most frequently used anticonvulsant for
neuropathic pain (60) .

Anecdotal
evidence points to a similar analgesic effect with lamotrigine (61 - 64) ,
although the evidence from the small number of RCTs so far reported is mixed (65,
66) . The analgesia from lamotrigine may be dose related and studies
reporting no analgesia used low dosing regimes of this drug.

Gabapentin,
a structural analogue of the inhibitory neurotransmitter gamma amino butyric
acid (GABA), which paradoxically is thought not to exert its effect on GABA
receptors (67) , has recently been demonstrated to reduce neuropathic pain (68 - 73) ,
and in particular post herpetic neuralgia (74) and
painful diabetic neuropathy (75) , both conditions being archetypal
neuropathic pain conditions. The
potential advantage of lamotrigine and gabapentin over carbamazepine are their
more favourable side effect profiles (76) .

When oral
dose titration is not possible then parenteral administration may be necessary.
Intramuscular fosphenytoin (a water soluble ester pro-drug of phenytoin,
lacking its infusion related side-effects) produces analgesia where neuropathic
pain is present (81) . Intravenous
infusions of phenytoin and fosphenytoin both have a similar analgesic effect
with the added advantage of relief that extends beyond the period of infusion
and the intravascular half-life of the drug (82, 83) .

Despite a
common effect (reduction in seizure frequency and analgesia), anticonvulsants
differ in their mode of action. Phenytoin
has a sodium channel blocking effect (77) while lamotrigine has an effect on voltage gated cation
channels (78) and
glutamate release (79) , while gabapentin appears to exert its action
via the alpha delta 2 sub unit of the calcium channel (80) .
The clinical consequence of these differing modes of action is that a
failed trial with one anticonvulsant does not mean that another in this class
will not work.

Baclofen

Baclofen,
like gabapentin, is structurally similar to the inhibitory amino acid gamma
amino butyric acid (GABA) and yet seems to have a mechanism of action that
differs to that of GABA (84, 85) .
It is known to depress release of the excitatory neurotransmitters
glutamate and aspartate (86, 87) .
Isolated studies suggest an analgesic effect in trigeminal neuralgia (88,
89) .

CCK Antagonists

The causes
of incomplete analgesia with opiates in neuropathic pain are many. Among them are elevation of the anti-opioid peptide
cholecystokinin (CCK) (90 - 92) .
Neural injury produces an elevation in plasma CCK levels (93) ,
and if a CCK antagonist is administered, then opiate sensitivity in neuropathic
pain may return. The obsolete
anti-ulcer drug proglumide is a non-specific CCK antagonist (94) and
has been shown to augment the analgesic effect of sustained release morphine in
neuropathic pain (95, 96) . As
well as reducing the analgesic effect of opiates, CCK is also elevated with
chronic opiate administration, and hence more opiate is required to achieve the
same level of analgesia with the passage of time (tolerance) (97 - 103) .
CCK antagonists such as proglumide can reverse this tolerance.
It may therefore be that opiates can be used to treat chronic neuropathic
pain when co-administered with a CCK antagonist, although the debate will
continue as to whether a dose limit be put on the sustained release morphine
preparation.

Membrane Stabilisers

For many
years intravenous infusions of local anaesthetics have been used in the
management of both acute and chronic pain: the analgesia of IV novocaine was
described in 1943 (104) .
Despite much anecdotal evidence of analgesia with IV lignocaine (105
- 8) there are few RCTs to
verify this effect. It does seem
that a short term infusion (e.g. 24 hours) may give relief in some patients for
a sustained period (weeks to months). Parenteral
local anaesthetics seem to suppress the activity of spontaneously active fibres
in neuromas (109), , depresses C - afferent fibre evoked
activity in the spinal cord (110) and
silence dorsal root ganglion discharge without blocking nerve conduction (111)
.

Parenteral
administration of local anaesthetics may not always be feasible and there is
some evidence to suggest that the oral equivalent mexiletene may also
have an analgesic effect (112 ) .

Ketamine

Ketamine, a
N-methyl D-aspartate (NMDA) receptor antagonist can have an analgesic effect in
neuropathic pain (113 - 4). Its
use is associated with side-effects that limit its use, but recent work has
suggested an opiate potentiating effect that may be apparent at otherwise
sub-therapeutic doses (115) .

Nerve blocks

The
perineural injection of drugs seems to produce pain relief in some patients with
neuropathic pain for varying lengths of time.
Local anaesthetic injection may give only short term relief.
However, the addition of corticosteroid may lengthen the pain relief
produced. Steroids reduce inflammation by reducing prostaglandin synthesis (116
) , suppress ectopic discharge (117) , have C fibre membrane
stabilising effects (118) and
stabilise the dorsal horn cell (119) and
any or all of these effects may contribute to the pain relief produced.
With the example of epidural steroid administration there is mixed
evidence with some reports claiming benefit (120) ,
while others suggest less significant benefit in terms of extent and duration of
relief (121 - 2)

The alpha
adrenoreceptor agonist clonidine has been used for many years as an
antihypertensive agent. When
administered by the epidural or intrathecal route it has an effect on the
descending noradrenergic pathways (123 - 4)
which produces analgesia (125 -
8) . Unfortunately oral administration is not associated with such
relief.

While many
other agents may be used in treating neuropathic pain, their use is not verified
by appropriate studies. It is hoped
that the rational use of drugs increases the chance of achieving analgesia in
the patient with neuropathic pain. However,
when one considers the "numbers needed to treat" (N.N.T.), that is the
numbers of patients needing to take the drug to achieve 50% reduction of that
symptom in one patient, for the medication used in neuropathic pain it is clear
that it is always greater than 2.5 (28,52) .
Consequently, no one therapeutic intervention is guaranteed of success.
This is similar to drugs used in nociceptive pain where the N.N.T. varies
from 3.1 with paracetamol 500mg / codeine 60mg, to 3.6 with paracetamol 600 or
500mg, to 9.1 with codeine 60mg (129) .
Consequently it may often be necessary to work ones way through a list of
treatment options before analgesia is achieved.
Inevitably any relief produced may be tempered by the associated
side-effects of that drug so that improvement in quality of life (pain
reduction, mood elevation, increased mobility, better sleep with minimal side
effects from treatment) is the therapeutic goal.
Poly pharmacy is a real danger, with patients staying on medication in
hope of relief when none is actually apparent.
Trials of medication for a defined period of time with assessment before
and after may be more appropriate.

Pharmacological
management will produce the desired analgesia in some, but not all, patients.
In those who fail to respond, other modalities of treatment may be
considered, ranging from behaviour modification and fostering of coping skills
to the more major invasive medical techniques.
It is still reassuring, however, to realise that in the future we have
the prospect of additional agents which may or may not prove useful analgesics
in neuropathic pain. These include
agents with more specific sodium channel blocking effects, calcium channel
blockers and new generation anticonvulsants and capitalise on the major
expansion in knowledge generated from the work of the basic scientists.

It is hoped
that this paper highlights the current outpatient therapeutic options and
demonstrates a rational approach to the management of the patient with
neuropathic pain.